Ethynylation of ketones and aldehydes to obtain alcohols

ABSTRACT

ETHYNYLATION OF KETONES AND ALDEHYDES BY ADDING ACETYLENE TO A SUSPENSION OF AN ALKALI METAL AMIDE IN A LIQUID ETHER, PARTICULARLY IN THE PRESENCE OF A STABILIZING AGENT, SUCH AS DIMETHYLACETAMIDE OR DIMETHYLSULFOXIDE, WHICH SERVES TO ACTIVATE THE FORMATION OF A MONOALKALI METAL ACETYLIDE AND TO STABILIZE SAID MONOALKALI METAL ACETYLIDE AND THEREAFTER HYDROLYZING TO OBTAIN AN ALCOHOL.

United States Patent 3,576,889 ETHYNYLATION 0F KETONES AND ALDEHYDES TOOBTAIN ALCOHOLS Kenneth R. Martin and Constantinos G. Screttas,Gastonia, N.C., assignors to Lithium Corporation of America, New York,N.Y. No Drawing. Filed Jan. 26, 1968, Ser. No. 700,692 Int. Cl. C07c33/04; C2311 /08 US. Cl. 260-638 Claims ABSTRACT OF THE DISCLOSUREEthynylation of ketones and aldehydes by adding acetylene to asuspension of an alkali metal amide in a liquid ether, particularly inthe presence of a stabilizing agent, such as dimethylacetamide ordimethylsulfoxide, which serves to activate the formation of amonoalkali metal acetylide and to stabilize said monoalkali metalacetylide and thereafter hydrolyzing to obtain an alcohol.

This invention relates to a novel method of ethynylation of carbonylcompounds selected from the group of ketones and aldehydes, and itinvolves the use of alkali metal amides, especially lithium amide (LiNHas a metalating agent in the formation, intermediate-wise, of amonoalkali metal acetylide, particularly monolithium, acetylide, incertain liquid media other than liquid ammonia.

It has heretofore been known to utilize alkali metal amides in liquidammonia as the reaction medium as, for instance, lithium metal has beenadded to liquid ammonia containing a catalyst such as Fe(NO or FeClwhereby a suspension of lithium amide is formed, whereupon acetylene isthen passed through said suspension to form a soluble monolithiumacetylide (LiCECH), which reacts with a ketone or aldehyde to ethynylatethe same (A. L. Henne and K. W. Greenlee, J. Am. Chem. Soc., 65, 2020(1943); 67, 484 (1945). Such procedure is a variation of the generalmethod of carrying out monolithium acetylide ethynylations in liquidammonia. The foregoing known methods of producing ethynylated ketonesand aldehydes have a number of objections which are effectively overcomeby the practice of our present invention, as will be pointed out in moredetail below.

We have discovered that certain reaction media, disclosed hereafter indetail, are distinctly more desirable than liquid ammonia for use inethynylation reactions utilizing lithium amide; that certain stabilzngagents are effectve to activate the formation of monoalkali metalacetylides and to stabilize them so that they can be used effectively asethynylating agents; and that certain of said stabilizing agents can beused in very small amounts, of the order of catalytic quantities, forinstance, 0.1 or 0.2 equivalent or less, per equivalent of alkali metalamide, and yet are effective to bring about high yields and, in certaincases, substantially quantitative yields of ethynylated ketones andaldehydes. More specifically, we have found that, in the presence ofcertain stabilizing agents, LiNH in certain liquid ether media, reactswith acetylene to form a stabilized monolithium acetylide (LlCECH) whichis capable of very efiectively ethynylating ketones and aldehydes, incertain cases producing yields of the corresponding ethynols (uponhydrolysis) of the order of 95 to 100%. The stabilizing agents which areespecially satisfactory are those which are characterized by a neutralto acid reaction (in aqueous medium) or, in other words, are non-basicin reaction.

We have, furthermore, produced certain novel catalyst systems which arespecially useful in ethynylation reactions such as are describedhereafter pursuant to the teachings of our present invention.

Patented Apr. 27, 1971 While the method of our invention is applicableto ethynaylations broadly of ketones and aldehydes utilizing alkalimetal amides and acetylene, in the manner hereafter disclosed, it will,for convenience, first be more particularly described in its especiallypreferred embodiments.

A slurry or suspension is made of LiNH in (a) a liquid ether, such astetrahydrofuran (TI-IF) or dimethoxyethane, (b) a stabilizer in the formof a liquid sulfoxide such as dimethylsulfoxide (DMSO) ortetramethylenesulfoxide, or a liquid amide such as dimethylacetamide(DMA), or mixtures of sulfoxides and amides. Then, acetylene is passedthrough said suspension in a volume in the range of about 100 to 1000%of the equivalent amount of acetylene in relation to the lithium amidein said slurry or suspension. During the reaction which occurs, ammoniais released and most of it is lost as a gas since ammonia is onlyslightly soluble in the reaction medium employed. Then the ketone oraldehyde is added dropwise as a neat liquid or, if a solid, as asolution preferably in a liquid ether, or, in certain cases, in a liquidhydrocarbon such as benzene or toluene which is miscible with the liquidether solvent, with desired temperature control, and the reaction iscarried out for a time necessary for the desired completion of theethynylation reaction. By way of illustration, where the ketone iscyclohexanone, a temperature of about 25 degrees C. for a period ofabout 2 hours is generally satisfactory; where the ketone is methylvinylketone, a temperature of about 25 degrees C. for a period of about 5minutes is generally satisfactory; and, where the aldehyde is acrolein,a temperature in the range of 50 to +30 degrees C. for a period of about2 to 3 hours in the lower temperature range and 5 minutes in the uppertemperature range is generally satisfactory. Yields under optimumconditions are commonly in the range of about to about The method of ourinvention has a number of advantages over the aforementioned knownliquid ammonialithium amide procedure in that:

(l) The reaction generally may be carried out much more rapidly, it isgenerally much cleaner, and little cooling is required;

(2) The yields of the product ethynols are generally greatly increased,commonly being close to quantitative;

(3) Recovery of the solvent and the stabilizing agent is simple; and

(4) Ethynylation of o e-unsaturated aldehydes such as acrolein can becarried out by our method, which is substantially impossible in liquidammonia.

The overall reaction scheme of our invention may be indicated as set outbelow, utilizing acetylene and a ketone:

(l) MeNHz HC CH Z MeC CI-LZD NH3 where Me is an alkali metal, especiallylithium, Z is stabilizing agent which, at least in certain instances,appears to form a complex with the monoalkali metal acetylide, and nrepresents the number of equivalents of Z used in the reaction and may,generally speaking, vary from about 0.01 to about 1 equivalent perequivalent of alkali metal amide used.

[I after hydrolysis MeC CELZn RCR R\ /OH /O\ Z MeOH R C CH where R and Rare the radicals which, together with the carbonyl group, represent aketone.

In the case of the use of dirnethyl sulfoxide as the stabilizing agent,the overall ethynylation reaction, using 3 methylvinyl ketone as thecarbonyl compound, is generally represented by the following equation:

2L1NH2 2HC CH OHsS OCHs (LiC OH)2.CHaSOCHa NH;

ll after hydrolysis LiC OH.CH3S 0 CH C1130 CH= CH2 (III) C E C H Amongthe various liquid ethers which can be used as the media in which thereaction is carried out are, by way of example, linear alkyl ethers suchas the dialkyl ether such as dimethyl ether, diethylether, di-n-propylether, diisopropyl ether, di-n-butyl ether and diisobutyl ether; dialkylethers of aliphatic polyhydric alcohols such as the dialkyl ethers ofalkylene glycols such as dimethyl ether of ethylene glycol, diethylether of ethylene glycol, diisopropyl ether of ethylene glycol,diisopropyl ether of diethylene glycol; dimethyl-, diethylanddiisopropyl ethers of propylene glycol; cyclic alkyl ethers such astetrahydrofuran (THF), tetrahydropyran (THP), dioxane, and 7- oxa[2,2,1]bicycloheptane (OBH); and liquid ethers which can be represented by theformula where R R and R are the same or different alkyl groups eachcontaining from 1 to 4 carbon atoms, namely, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, and tertiarybutyl; and x is a nonreactivegroup such as methoxyethane.

The stabilizing agents, as indicated above, include normally liquidsulfoxides having the formula in which R is alkyl (including cycloalkyl)containing from 1 to 12 carbon atoms, R is alkyl containing from 1 to 12carbon atoms or aryl or aralkyl hydrocarbons containing from 6 to 9carbon atoms, or R and R together form an alkylene group as intetramethylene sulfoxide. Thus, R and R can be methyl, ethyl, propyl,isopropyl, butyl, isobutyl, amyl, isoamyl, hexyl, cyclohexyl; or aryl oraralkyl hydrocarbon such as phenyl as in diphenylsulfoxide, or benzyl asin dibenzylsulfoxide; or R can be alkyl and R can be aryl as inmethylphenylsulfoxide, or benzyl as in methylbenzylsulfoxide; or R canbe lower alkyl (C to C and R can be higher alkyl (C to C as inmethyldodecylsulfoxide, isopropyldecylsulfoxide, and the like.Especially satisfactory among the sulfoxides is dimethylsulfoxide(DMSO).

4 The amide stabilizing agents can, in the main, be represented by theformula in which R is hydrogen or alkyl (including cycloalkyl), and Rand R are each alkyl (including cycloalkyl), aryl or aralkyl, the alkyladvantageously containing from 1 to 6 carbon atoms, and the aryl andaralkyl containing from 6 to 9 carbon atoms such as phenyl,methylphenyl, isopropylphenyl and benzyl. The amides are generallydesirably normally liquids at room temperature, illustrative examples ofwhich are dimethylformamide (DMF), dimethylacetamide (DMA),diethylacetamide, diisopropylacetamide, diphenylacetamide anddibenzylacetamide. DMA is especially satisfactory among the amidestabilizing agents and it usually an be employed in low quanties, of thegeneral order of 0.1 to 0.2 equivalent per equivalent of LiNH We havealso found that hexa-alkylphosphoramides such as hexamethylphosphoramide[(CH N] P=O and hexaethylphosphoramide [(C H )N] P=O and we have alsofound that such compounds as Z-aminoethanol; 2- pyrrolidone; and1-methyl-2-pyrrolid0ne are useful stabilizing agents for the purposes ofour present invention.

It will be understood, of course, that not all of the stabilizing agentswhich are disclosed herein will give the same or substantiallyequivalent results with all ketones or all aldehydes so far as percentyield or conversion to the respective ethynols are concerned. It willalso be understood that, in general, concentrations of reactants plays arole in the yields obtained, and the same is true with respect toreaction times. For optimum yields in any given case, these factors canreadily be determined in the light of the teachings contained herein.Thus, by way of illustration, in the case of methylvinyl ketoneethynylations, DMSO, DMA, and hexamethyl phosphoramide have been foundto be particularly satisfactory. DMA and N-methylpyrrolidone (NMP)generally have the advantage of being useful in distinctly less thanstoichiometric amounts, for instance, even as low as about 0.1 or 0.2equivalent per equivalent of LiNH Indeed, in the case of DMA, using LiNHand THF as the ether medium, and ethynylating methylvinyl ketone, theoptimum concentration for the DMA is generally about 0.11 to 0.2equivalent with a reaction time of somewhat less than 3 minutes at 25-30degrees C. for the production of methylvinylethynyl carbinol. However,higher amounts of DMA, ranging up to about 1 equivalent thereof perequivalent of LiNH also give excellent yields. Thus, in illustrativeruns in which methylvinyl ketone, in a 0.5 M solution of monolithiumacetylide in THF, was ethynylated in a reaction medium to which LiNH andDMA were added and acetylene gas bubbled therethrough, the yields ofmethylvinylethynyl carbinol, after hydrolysis of the ethynylatedproduct, were as follows using varying equivalents of DMA:

Equivalents of Percent DMA yield The foregoing situation would appear toindicate that DMA does not form a complex with the ethynolate or formsonly a weak complex and is, therefore, still available to complex themonolithium acetylide. In regard to the mechanism of the reaction orreactions which occur when acetylene is bubbled through a LiNH -DMAmixturei n THF, Which said mechanism has not been fully established, itis believed that a complex of monolithium acetylide is formed with theDMA only to the extent that the monolithium acetylide can be stabilizedby the DMA, and then further formation of monolithium acetylide waitsuntil DMA is released in the ethynylation reaction.

Still further, by way of illustration, in ethynylating methylvinylketone, utilizing LiNH DMSO and acetylene, in the practice of thepresent invention, a concentration of at least 0.5 and up to 1equivalent of DMSO gives excellent yields of methylvinylethyl carbinol,0.5 equivalant of DMSO per equivalent of LiNH producing a yield of 100%and 1 equivalent of DMSO producing a yield of 92% in certain reactionsso carried out. On the other hand, using 0.2 equivalent of DMSO gave ayield of only about 25% of the methylvinylethynyl carbinol. It may benoted, in the case of DMSO, that LiNH itself reacts therewith only veryslowly at 25 degrees C.

The desired reactions, in accordance with the present invention, willnot take place unless the activator, for example DMSO or DMA, which,also, commonly functions as a complexing agent, is present in theenvironment in which the method of the present invention is carried out.

While the invention is most advantageously carried out using lithiumamide, particularly because the ammonia which formed is highly volatileand can readily be removed so as not to interfere with the treatmentparticularly of sensitive ketones where basicity is very detrimental,other lithium amides can be used although, as indicated, generally withdistinctly lesser advantage. Such other lithium amides include, forinstance, lithium diethylamide, lithium diisopropyl amide, lithiumdibutyl amide and lithium diisobutyl amide. Further, as previouslyindicated, other alkali metal amides can be used such as sodium amide,potassium amide, rubidium amide and cesium amide as well as the otheraforementioned diloweralkylamides but of the alkali metals other thanlithium.

The method of the present invention is applicable to the ethynylation ofketones and aldehydes generally, of aliphatic (including cycloaliphatic)or aromatic character, saturated and unsaturated such as alkanones,alkenones, alkanals and alkenals. Illustrative of such ketones areacetone, methylethyl ketone, methyl n-propyl ketone, diethylketone,di-n-propyl ketone, diisopropyl ketone, din-butyl ketone, diisobutylketone, methyl-t-butyl ketone, di-n-amyl ketone, diisoamyl ketone,diacetyl, hexanone, cyclopentanone, cyclohexanone, isophorone,benzophenone, mesityl oxide, methylbenzyl ketone; 17-keto steroids, forinstance, estrone which, on ethynylation, produces ethynylestradiol, andsimilar 17-keto steroids which, on ethynylation, produce 17 fi-ethynylsteroids such as mestranol and analogous compounds; and ethylfl-chlorovinyl ketones which, on ethynylation, produces Placidyl; andillustrative of such aldehydes are formaldehyde, acetaldehyde, glyoxal,propionaldehyde, n-butyraldehyde, isobutyraldehyde, n-valeraldehyde,isovaleraldehyde, ncaproaldehyde, n-heptaldehyde, lauryldehyde,myristaldehyde, acrolein, crotonaldehyde, furfural, benzaldehyde,fl-naphthaldehyde, glyceraldehyde, and aldehydes of other diandpolyhydric aliphatic alcohols. It may be noted that, depending upon thenature of the a,B-unsaturated ketones and aldehydes, the ethynylationreaction may produce 1,2- or 1,4-addition, that is, the production ofvinyl ethynols or Z-ethynyl aldehydes or ketones or their ethynylationproducts.

In connection with the ethynylation of aldehydes, it may be noted thatit has heretofore been known that saturated aldehydes can be ethynylatedto produce ethynylation reaction products in quite high yields usingmonosodium acetylide in a suitable solvent. However, when OS-unsaturated aldehydes are similarly ethynylated, poor yields are thegeneral rule, just as is the situation with unsaturated ketones [Hennionand Lieb, J. Am. Chem. Soc. 66, 1289 (1944)]. As illustrative of thedifliculties of ethynylating acrolein, reference is made to U.S. Pat.No. 2,879,308 where the method involves protecting the vinyl group ofthe acrolein against polymerization by reversibly forming a Diels-Alderadduct with a diene, such as cyclopentadiene, and then ethynylating saidadduct with monosodium acetylide, the method taking 16 hours, involvingheating the product to 370-400 degrees F. to reverse the adductformation, and producing only a 31% yield of the alkynol.

In accordance with the present invention, by way of illustration,acrolein has been ethynylated directly in a LiNH -DMA-THF system inyields of the order of to 98.5% (vinylethynyl carbinol). Generallyoptimum conditions in this system are the use of DMA in about 0.1 to 0.2equivalent amount, reaction temperatures of 25 to 30 degrees C., andreaction times of 2 to 5 minutes. Good yields have also been obtained,for instance, in the ethynylation of crotonaldehyde, benzaldehyde, andtranscinnamaldehyde, and other unsaturated aldehydes, as well asunsaturated ketones, by quite simple procedures and in short reactiontimes.

The following examples are illustrative of the practice of theinvention, but they are not to be construed as in any way limitativethereof since various changes can readily be made in the light of theguiding principles and teachings disclosed herein. All temperaturesrecited are in degrees centigrade.

EXAMPLE 1 LiNH (1.2 g., 0.05 mol) was suspended in ml. of THF in a 250ml. 3-necked, nitrogen-swept flask equipped with magnetic stirrer,nitrogen inlet, dropping funnel and an inlet tube for acetyleneextending below the surface of the liquid. DMA (0.44 g., 0.005 mol) Wasintroduced into the mixture. Acetylene was bubbled through the reactionmixture at a rate of 144 ml./min. After 15 minutes, dropwise addition ofmethylvinyl ketone (3.4 g., 0.045 mol) was begun. The addition rate wascontrolled so that the reaction temperature did not rise above 35degrees, using external cooling if necessary. Acetylene passage wascontinued throughout the addition period, either at the same rate or ata reduced rate, say, half the initial rate. The reaction time with themethylvinyl ketone was equal to the addition time which, in turn, wasset so that the reaction temperature did not exceed about 35 degrees.External cooling can be utilized so that the addition rate can beincreased. Immediately after the ketone addition was completed, and, inany event, generally within a period of a few minutes after thecompletion of the ketone addition, the reaction mixture was hydrolyzedby pouring it over a mixture of ice and concentrated acetic acid, beingcareful that the pH of the hydrolysis mixture was below 7 at all times.Sodium chloride was added to salt out the alkynol, and the mixture wasneutralized with NaHCO The mixture was then extracted twice with diethylether, and the combined ether layers were dried and weighed. Titrationof a 0.3 g. sample of the solution with excess 5% alcoholic AgNO andback-titration with 0.1 N NaOH to the methylene blue endpoint gave ayield of 4.43 g. (98%) of methylvinylethynyl carbinol, B.P. 60 degrees(60 mm.).

EXAMPLE 2 LiNH (1.2 g., 0.05 mol) was suspended in 100 ml. of THF in a250 ml. 3-necked, nitrogen-swept flask equipped with magnetic stirrer,nitrogen inlet, dropping funnel and an inlet tube for acetyleneextending below the surface of the liquid. DMSO (1.95 g., 0.025 mol) wasintroduced.

Acetylene was bubbled through the reaction mixture at the rate of 144mL/min. After 20 minutes (a 100% excess of acetylene being added)dropwise addition of methylvinyl ketone (3.4 g., 0.045 mol) was begun.The addition rate was controlled so that the reaction temperature didnot rise above 35 degrees, using external cooling if necessary.Acetylene passage was continued throughout the addition period asdescribed in Example 1. Immediately after the ketone addition wascompleted, the reaction mixture was hydrolyzed by pouring it over amixture of ice and concentrated acetic acid, being careful that the pHof the hydrolysis mixture was below 7 at all times. Sodium chloride wasadded to salt out the alkynol and the mixture was neutralized with NaHCOThe mixture was then extracted twice with diethyl ether, and thecombined ether layers were dried and weighed. Titration of a 0.3 g.sample of the solution with excess alcoholic AgNO and back-titrationwith 0.1 N NaOH to the methylene blue endpoint gave a yield of 4.46 g.(99%) of methylvinylethynyl carbinol, B.P. 60 degrees (60 mm.).

EXAMPLE 3 Except as indicated below, the reactants in the proportionsset out below were reacted in the manner described in Example 1:

500 ml. of THF 5.9 g. (0.25 mol) LiNH 4.3 g. (0.05 mol, 0.20 equiv.) DMA17.2 g. (0.0247 mol) methylvinyl ketone External cooling was used tokeep the reaction temperature in the 27 to 30 degrees range. Thereaction mixture was stirred for 5 minutes after the ketone was addedand then hydrolyzed. The workup procedure was modified in that allextractions and washings were made with measured amounts of THF ratherthan with ether. Hydroquinone was added to the hydrolysis mixture toprevent polymerization. The dried THF extract was stripped in a rotaryevaporator at 100 mm. pressure and the THF collected in a trap. Therecovery was 92.5%. Methylvinyl alkynol was isolated by distillation at60 degrees (60 mm.) to give 18.4 g. (82% dist. yield); the yield bytitration was 96%, giving an isolation of 86% of the alkynol based onthat formed in the reaction. In addition, the distillation afforded ahigher boiling fraction which was recovered DMA, 1.9 g. (43%). GLCanalysis of the aqueous layer from the hydrolysis revealed that most ofthe remaining DMA was present there (1.4102 g.). From the foregoing, itis clear that good recoveries of alkynol and solvent are obtained, andabout half of the complexing agent can be recovered easily; the part inthe aqueous layer is more diflicult to recover.

EXAMPLE 4 1.2 g. (50 millimoles) of LiNH and 0.87 g. millimoles) of DMAor 0.96 g. 10 millimoles) of NMP were placed in 100 ml. of THF in anitrogen-swept 250 ml. flask. Acetylene was bubbled through the mixturefor 20 minutes at a rate of 200 mL/min. The rate of acetylene additionwas then reduced to 140 ml./min. and 4.3 g. (50 millimoles) ofcyclopentanone were added rapidly. The reaction temperature rose byabout 8 to 10 degrees during the addition and the previously whitereaction mixture turned bright yellow at the end of the addition. Thereaction mixture was stirred, with continued acetylene passage, for therequired reaction period. It was then hydrolyzed by pouring over amixture of ice and acetic acid sufiicient to give a neutral or slightlyacidic solution at the end of the hydrolysis. Solid NaCl was added tothe mixture, and it was neutralized (if necessary) with a saturatedNaHCO solution. The mixture was extracted twice with ether and theextracts were dried with Na SO and weighed. An aliquot of about 0.3 g.was taken and titrated with alcoholic AgNOg, then back-titrated with 0.1N NaOH. The conditions, yields and results of a series of 8 suchexamples with certain variations are summarized in the following TableI.

EXAMPLE 5 0.6 g. (25 millimoles) of IiNH and 0.22 g. (2.5 millimoles) ofDMA were placed in 100 m1. of THF in a 250-ml. nitrogen-swept flask.Acetylene was bubbled through the mixture for 20 minutes at a rate of200 ml./ min. The rate was then reduced to 140 ml./min. and 2 g. ofcyclopentanone (22.5 millimoles) were added rapidly. The reactiontemperature rose 5-7 degrees during the addition and maintained itselffor 10 minutes after the addition was complete, the reaction mixturebecoming bright yellow. The reaction mixture was stirred for 30 minutesafter the addition of the ketone was complete and then hydrolyzed andworked up as previously described. The results are summarized in TableI.

TABLE I.ETHYNYLATION OF OYCLOPENTANONE IN THF USING LiNH2 EquivalentStabilizing of stabilizing Concentraand comand tion of plexlngcomplexlng solution Time at Percent agent agent mols/liter 25, hrs.yield 0. 2 0.5 1. 5 72 0. 2 0.5 0.5 70 0.2 0.5 0.5 70 0.2 0. 5 1. 5 640.1 0. 5 2.0 65 0.1 0. 5 0. 5 0. 2 0. 5 0. 5 84 0.1 0.5 1 77 0. l 0. 5 15 77 0. 1 0. 5 0. 5 S6 0. 5 0. 5 0.25 77 0.1 0.5 a 0.25 70 0.1 0.25 0. 593 1 Minutes. 2 10% excess of L1NH2. 3 35.

EXAMPLE 6 (a) To 20 ml. of THF in a 100 m1. nitrogen-swept flask wereadded 0.5-0.6 g. (excess) of LiNH and 0.1 g. (0.0011 mol) of DMA.Acetylene was bubbled through the mixture at a rate of 140 ml./min.After 15 minutes, 0.3 g. of estrone (0.0011 mol) dissolved in 40 ml. ofTHF were added rapidly and the reaction mixture was stirred for 4 to 5hours at room temperature with con tinuous acetylene passage. At the endof the reaction peri- 0d, the acetylene was turned off and the reactionmixture hydrolyzed over a mixture of ice and acetic acid. The mixturewas neutralized and extracted several times with ether. The combinedextracts were dried over anhydrous Na SO and the solvent was removedunder reduced pressure, leaving a pale yellow oil as residue. The oilwas taken up in methanol and the product was precipitated by adding anequal volume of hot water. Filtration gave crude estradiol, which wasdried in a vacuum desiccator overnight, giving white crystals of17p-ethynylestradiol, M.P. 132-5 degrees. Recrystallization from 1:1methanol-water gave a product with an M.P. of 143-4 degrees. Productyield was about 82% (b) In another run following the procedure of part(a) of this Example 6 except that 0.1 equivalent of DMA was used insteadof the approximately 1 equivalent in part (a) and a 5 hour reactionperiod was used instead of 4.5 hours in part (a), product yield wasabout EXAMPLE 7 A number of runs was made in which various unsaturatedaldehydes were ethynylated utilizing the following general procedure. InTable II, the results of such runs are set forth.

To ml. of THF in a nitrogen-swept 250 ml. flask were added 0.65 g. (25millimoles) of LiNH and 0.22 g. (2.5 millimoles) of DMA. A stream ofacetylene was bubbled through the suspension at a rate of 200 ml./min.for 15 to 20 minutes, then at a rate of ml./min. for

the remainder of the reaction period. Neat aldehyde (22.5 millimoles)was then added dropwise over 2 to 3 minutes. The reaction temperaturerose by 9 to degrees. Within 3 minutes of the end of the aldehydeaddition, the reaction mixture was hydrolyzed by pouring over a mixtureof ice and an amount of acetic acid sufficient to just neutralize thebase present (about 3.5 ml.). Solid NaCl was added to the mixture, andit was extracted twice with ether. The combined ether layers were driedover anhydrous Na SO and weighed. Analysis was by titration of 0.3 to0.5 g. sample with excess AgNO followed by back-titration with 0.1NNaOI-I to the methylene blue endpoint. Except as noted below, samplesfor distillation were obtained by stripping most of the low-boilingmaterial in a flash evaporator, followed by a short-path distillation ofthe residue into a liquid-nitrogen trap to remove polymeric material.The crude alkynol was then fractionated.

Runs Nos. A, B, C and D each involved the ethynylation of acrolein. RunNo. E involved the ethynylation of benzaldehyde. Run No. F involved theethynylation of crotonaldehyde. Runs G, H and I involved theethynylation of trans-cinnamaldehyde.

TABLE II Percent Temp., Time yield Cone, M (min.) (titration) 1 Reactionmixture not distilled; distillation resulted in production ofsemi-crystalline polymeric material.

LiCEOH 0.1 DMA.

In the runs of Example 7, it will be noted that high yields wereobtained at approximately room temperature with short reaction times,and that high yields (Run No. A) were also obtained at very lowtemperatures but with longer reaction times. It may also be pointed outthat, in Runs A, B, C and D, it was noted that the development of abright yellow color in the reaction indicated the end of the reaction,and that no further temperature rise occurred hereafter. For example, ifthis point occurred when 75% of the aldehyde had been added, only a 75yield of ethynol was obtained. On the other hand, quantitative yieldswere obtained when no coloration occurred before all of the aldehyde wasadded. The reaction appeared to go best to completion when the reactiontemperature was allowed to rise above 27 degrees from the heat ofreaction. If the rate of addition was slow, or if addition of thealdehyde was stopped for a short time, the reaction stopped. The rate ofaddition should be rapid enough so that the reaction is maintained;temperatures as high as 3335 degrees during addition did not adverselyaffect the yield. The cause of the foregoing phenomenon is notdefinitely known, but is thought that it is due to formation of acomplex between the lithium ethynolate and DMA, removing the activatorfrom the reaction and thus stopping it. In the case of DMSO as theactivator, it is thought that a strong complex is formed with theethynolate, necessitating the use of an equivalent of activator; withDMA, there appears to be a competition between monolithium acetylide andthe ethynolate, which favors the acetylide at higher temperatures,allowing the use of less than stoichiometric amounts of activator. Theseobservations concerning the mechanisms which may be involved are notintended as being definitive of the reactions which may occur and arenot to be construed as affecting in any manner the final results whichare obtained by virtue of the procedures which have been described toachieve the advantages brought about by the present invention.

Particularly when working with relatively large quantities of reactants,especially in the ethynylation of acrolein or similar cap-unsaturatedaldehydes, to produce vinylethynyl carbinol, the reaction from thehydrolysis to the first distillation should be carried out in as short atime as possible to avoid polymer formation since the latter occursfairly rapidly in the impure reaction mixture. The purified distillate,however, can be stored prior to fractionation. Furthermore, thehydrolysis mixture should not be allowed to become basic but it shouldbe either acid or neutral. Finally, as indicated previously, theaddition of the acrolein to the reaction mixture should be suflicientlyrapid to keep the reaction from stopping. A reaction temperature ofabout 30 to 33 degrees appears to be generally optimum in the case ofthe ethynylation of acrolein. In ethynylating acrolein, as in the caseof the ethynylation of methylvinyl ketone, there is a concentrationeffect, the yield decreasing with increasing concentrations abovecertain limits.

Other examples have been carried out in accordance with our invention inwhich the following carbonyl compounds have been ethynylated using LiNHin a THF medium and wherein the stabilizing (complexing) agents wereDMSO and DMA with the following results:

Percent yield ethynol Still other examples have been carried out inwhich the following carbonyl compounds have been ethynylated usingLiNI-I in a THF medium and wherein the stabilizing (complexing) agentwas ethylenediamine (EDA) with the following results:

Equiv. of Percent yield alkynol EDA Carbonyl compound compound 1Methylvinyl ketone 5 3 0.1 Methylvinyl ketone 65 0.1 Diisopropyl ketone82 The lower yield of ethynol obtained from methylvinyl ketone using 1equivalent of EDA than in the case where 0.1 equivalent was used isbelieved to be due to the basic character of EDA, it being noted thatmethylvinyl ketone and the ethynol are quite sensitive to base-catalyzedside reactions in the THF-EDA system. This conclusion appears to besupported by the fact that, in the case of the ethynylation ofdiisopropyl ketone, which is much less susceptible to base attack thanis methylvinyl ketone, a yield of 82% of the alkynol was obtained. Inany event, it is clear that DMA is distinctly superior to EDA withrespect to activation of the ethynylation reaction.

Such ethynylation reaction products of the present invention as, forexample, methylvinylethynyl carbinol, are useful as intermediates in theproduction of Vitamin A and Vitamin A-like products and otherpharmaceuticals by procedures which are well known to the art. Theethynylation reaction products made in accordance with this inventionare also of utility as brightening agents in electroplating baths forthe electroplating of nickel, being used in the manner described, forinstance in U.S. Pat. No. 2,712,522, being water-soluble acetylenicalcohols.

We claim:

1. In a method of preparing alcohols, the steps which comprise providinga suspension of (a) an alkali metal amide in (b) a liquid ether andcontaining (c) a stabilizing agent effective to activate the formationof a monoalkali metal acetylide, adding acetylene to said suspension toconvert a portion of the alkali metal amide to a stabilized monoalkalimetal acetylide, adding (d) a carbonyl compound to said stabilizedmonoalkali metal acetylide in admixture with unconverted alkali metalamide while continuing to add acetylene and thereafter hydrolyzing, said(a) ingredient being selected from the group of alkali metal amides andalkali metal diloweralkylamides; said (b) ingredient being selected fromthe group of dialkyl ethers, dialkyl ethers of alkylene glycols,tetrahydrofuran, tetrahydropyran, dioxane; 7-oxa (2,2,1)-bicycloheptane;liquid ethers represented by the formula R2 where R R and R are the sameor different alkyl each containing from 1 to 4 carbon atoms, and X islower alkylene; said (c) ingredient being selected from the group ofnormally liquid sulfoxides having the formula s=o in which R is alkyl(including cycloalkyl) containing 1 to 12 carbon atoms or aryl oraralkyl hydrocarbons containing from 6 to 9 carbon atoms, or R and Rtogether form an alkylene group; amides represented by the formula inwhich R is hydrogen or alkyl (including cycloalkyl), and R and R areeach alkyl (including cycloalkyl), aryl or aralkyl, the alkyl containingfrom 1 to 6 carbon atoms, and the aryl and aralkyl containing from 6 to9 carbon atoms; hexamethylphosphoramide, hexaethylphosphoramide,Z-aminoethanol; 2-pyrrolidone; and 1-methyl-2- pyrrolidone; and said((1) ingredient being selected from the group of alkanones, alkenones,alkanals, alkenals, diacetyl, cyclopentanone, cyclohexanone, isophorone,benzophenone, methylbenzyl ketone; estrone; ethyl B-chlorovinyl ketone,furfural, benzaldehyde, B-naphthaldehyde and glyceraldehyde.

2. A method according to claim 1, in which the alkali metal is lithium.

3. A method according to claim 2, in which the stabilizing agent is ofnon-basic character.

4. A method according to claim 2, in which the stabilizing agent isdimethylacetamide.

5. A method according to claim 2 in which the stabilizing agent is anormally liquid sulfoxide having the formula in which R is alkylcontaining from 1 to 12 carbon atoms, R is alkyl containing 1 to 12carbon atoms or aryl or aralkyl hydrocarbon containing from 6 to 9carbon atoms, or R and R together form an' alkylene group.

6. A method according to claim 5, in which the stabilizing agent isdimethylsulfoxide.

7. A method according to claim 2, in which the liquid ether istetrahydrofuran.

8. A method according to claim 3, in which the liquid ether istetrahydrofuran.

9. A method according to claim 2, in which the ketone is methylvinylketone.

10. A method according to claim 7, in which the aldehyde is an cd-unsaturated aldehyde.

12 11. In a method of preparing alcohols, the steps which compriseproviding a suspension of (a) lithium amide in (b) tetrahydrofuran andcontaining (c) a non-basic activating agent to activate the formation ofmonolithium .acetylide, adding acetylene to said suspension to convertR1 in which R is alkyl (including cycloalkyl) containing from 1 to 12carbon atoms, R is alkyl containing from 1 to 12 carbon atoms or aryl oraralkyl hydrocarbons containing from 6 to 9 carbon atoms, or R and Rtogether form an alkylene group; and amides represented by the formula 0R2 R1C /N s in which R is hydrogen or alkyl (including cycloalkyl), andR and R are each alkyl (including cycloalkyl), aryl or aralkyl, thealkyl containing from 1 to 6 carbon atoms, and the aryl and aralkylcontaining from 6 to 9 carbon atoms; hexamethylphosphoramide,hexaethylphosphoramide, Z-aminoethanol; 2-pyrrolidone; and l-methyl-2-pyrrolidone; and said (d) ingredient being selected from the group ofalkanones, alkenones, alkanals, alkenals, diacetyl, cyclopentanone,cyclohexanone, isophorone, benzophenone, methylbenzyl ketone; estrone;ethyl fl-chlorovinyl ketone, furfural, benzaldehyde, ,B-naphthaldehydeand glyceraldehyde.

12. The method of claim 11, in which the (d) ingredient is methylvinylketone.

13. The method of claim 11, in which the (d) ingredient is acrolein.

14. The method of claim 13, in which the activating agent isdimethylacetamide.

15. The method of claim 14, in which the dimethylacetamide is present inan amount in the range of 0.1 to 1 equivalent per equivalent of lithiumamide.

References Cited UNITED STATES PATENTS 2,106,181 1/1938 Kreimeier260638Y 2,777,884 l/1957 Rutledge et al. 260-638Y 2,879,308 3/1959'Pasedach et al. 260-638Y 2,919,281 12/1959 Chodroff et al. 260638Y2,925,363 2/1960 Bevley et al. 260-638Y 3,028,423 4/1962 Blumenthal260--638Y 3,470,217 9/1969 Ginsig 260632 OTHER REFERENCES Beumel et al.,J. Org. Chem, vol. 29 (1964), pp. 1872 to 1876.

BERNARD HELFIN, Primary Examiner J. E. EVANS, Assistant Examiner U.S.Cl. X.R.

